Inactivation of p53 in normal human cells increases G2/M arrest and sensitivity to DNA-damaging agents.
p53 mutations are found in about 70% of human cancers. In order to evaluate the role of these mutations in response to chemotherapeutic agents, it is important to distinguish between p53 response to DNA-damaging agents in normal and in tumour cells. Here, using normal human fibroblasts (NHFs), we show that cisplatin and UV radiation induce G2/M arrest which is temporally linked to p53-protein induction. To study the contribution of p53 to this G2/M arrest, we inhibited p53 induction in NHFs using p53 anti-sense oligonucleotides. Following exposure of NHFs to UV radiation, the inhibition of p53-protein induction leads to a greater accumulation of cells in the G2/M phase, but also to a decreased fraction of cells in the G1 phase. We propose that p53 does not induce G2/M arrest directly, and that the extent of this arrest may depend on the fraction of cells that do not stop at the G1 phase following exposure to DNA-damaging agents. Furthermore, inhibition of p53-protein induction leads to increased sensitivity of NHFs to UV radiation. These results suggest that inhibition of p53 protein enhances sensitivity to DNA-damaging agents in normal human cells.
Céraline
J
J
Laboratoire d'Oncologie Moléculaire, Institut de Recherche contre les Cancers de l'Appareil Digestif, Hôpitaux Universitaires de Strasbourg, France.
Deplanque
G
G
Duclos
B
B
Limacher
J M
JM
Hajri
A
A
Noel
F
F
Orvain
C
C
Frébourg
T
T
Klein-Soyer
C
C
Bergerat
J P
JP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D008969:Molecular Sequence Data; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014466:Ultraviolet Rays / Q000009:adverse effects
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D004247:DNA; D002945:Cisplatin